Experimental models of yeast, nematodes, fruit flies, and rodents indicate that aging and longevity are, in part, under genetic control. The nematode C. elegans, has provided genetic and biochemical evidence that identifies candidate genes that govern longevity. This involves attenuation of the daf-2, age-1 and daf-16 genes whose homologies to the mammalian-insulin receptor (InR) family and signaling pathway suggest that this pathway(s) may regulate metabolic characteristics that favor vertebrate longevity. The mouse dwarf mutants Snell (dw/dw), Ames (df/df) and little (lit/lit), live significantly longer than their normal siblings. The nature of the dwarf mutations, i.e., growth hormone (GH), thyroid stimulating hormone (TSH) and prolactin (Prl) deficiencies may result in physiological characteristics similar to those of the long-lived C. elegans mutants. Since these mice are the only vertebrate genetic models of longevity, and since the physiological characteristics of the "anti-aging" processes of the nematode and the long-lived dwarf mutants are strikingly similar, these mice provide an excellent resource to study the molecular and genetic processes that determine longevity in vertebrates. In this research program we will determine whether the physiological characteristics of the Snell and lit dwarf mice are longevity-determining factors of vertebrate aging. Specific Aims 1 will determine whether the Snell and lit mice exhibit such characteristics of delayed senescence as a reduction-of-function phenotype due to GH, insulin and IGF-I deficiency; immunological function; and regulation of stress response genes. In Specific Aim 2 we plan to use endocrine supplementation to determine the specific role of TH and Pr1 deficiencies as longevity-determining factors; In Specific Aim 3 we will determine the role GH deficiency in longevity using conditional transgenic Snell dwarf and lit mice in which GH expression is regulatable i.e., turned on or off at will. Our long-range goal is to elucidate the molecular and genetic basis of vertebrate life span by identifying the longevity-determining factors. Achieving these aims will identify pathways involving longevity and lay down foundations for understanding the mechanism by which these pathways act.